Asymmetric catalytic decarboxylative alkyl alkylation using low catalyst concentrations and a robust precatalyst

ABSTRACT

This invention provides efficient and scalable enantioselective methods that yield 2-alkyl-2-allylcycloalkyanone compounds with quaternary stereogenic centers. Methods include the method for the preparation of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     comprising treating a compound of formula (II) or (III): 
     
       
         
         
             
             
         
       
     
     with a palladium (II) catalyst under alkylation conditions.

RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application62/139,522, filed Mar. 27, 2015, the content of which is incorporatedherein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under Grant NumberGM080269, awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

The catalytic enantioselective construction of all-carbon quaternarycenters represents a considerable challenge in synthetic organicchemistry.^([1,2]) A new carbon-carbon bond must be formed in the faceof significant steric hindrance to accomplish this goal.

Synthetic methods for the generation of quaternary stereocenters areextremely desirable given their prevalence in a broad variety ofbiologically active natural products.^([2]) Despite their importance,the number of highly enantioselective transformations that constructquaternary stereocenters under mild reaction conditions is limited. Thepalladium-catalyzed decarboxylative asymmetric allylic alkylation is apowerful and reliable approach to bridge this gap.^([3])

However, despite the importance of palladium-catalyzed decarboxylativeasymmetric alkylation in total synthesis, its application on anindustrial scale is often hampered by the need for high catalystloadings (5.0-10.0 mol %). The high cost of palladium significantlyincreases the cost of each reaction. Furthermore, high catalyst loadingsalso increase the risk of poisoning downstream chemistry orcontaminating active pharmaceutical ingredients.^([4])

These drawbacks have discouraged application of the enantioselectiveallylic alkylation on a larger scale. The application of transitionmetal catalysis to industry-scale synthesis requires transformationsthat are safe, robust, cost-effective, and scalable.^([5]) Consequently,there remains a significant need to develop new reaction protocols thatemploy lower catalyst concentrations and hence facilitate the scale-upof such transformations.

SUMMARY OF THE INVENTION

The present invention provides methods for preparing a compound offormula (I):

comprising treating a compound of formula (II) or (III):

or a salt thereof;

-   with a Pd(II) catalyst under alkylation conditions, wherein, as    valence and stability permit,-   R¹ represents hydrogen or substituted or unsubstituted alkyl,    alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkoxy, amino, or halo;-   R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected    for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl,    alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    thioalkyl, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and    (heterocycloalkyl)alkyl;-   W represents, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—, —C(O)—,    —CR⁷═, or —N═;-   R⁶ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   R⁷ and R⁸ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether,    ester, amido, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;-   or R⁶, R⁷, and R⁸ taken together with a substituent on ring A and    the intervening atoms, form an optionally substituted aryl,    heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or    heterocycloalkenyl group;-   R¹⁰ and R¹¹ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl; and-   ring A represents an optionally substituted cycloalkyl,    heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl group.

The present invention further provides methods for preparing a compoundof formula (I):

comprising treating a compound of formula (IV) or (V) or a salt thereof:

with a compound of formula (X):

and

-   a Pd(II) catalyst under alkylation conditions, wherein, as valence    and stability permit,-   R¹ represents hydrogen or substituted or unsubstituted alkyl,    alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkoxy, amino, or halo;-   R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected    for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl,    alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    thioalkyl, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and    (heterocycloalkyl)alkyl;-   W represents, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—, —C(O)—,    —CR⁷═, or —N═;-   R⁶ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   R⁷ and R⁸ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether,    ester, amido, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;-   or R⁶, R⁷, and R⁸ taken together with a substituent on ring A and    the intervening atoms, form an optionally substituted aryl,    heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or    heterocycloalkenyl group;-   R¹⁰ and R¹¹ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl;-   ring A represents an optionally substituted cycloalkyl,    heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl group;-   R^(a) represents optionally substituted alkyl, aryl, or alkoxyl; and-   X represents a halide, carbonate, sulfonate, acetate, or    carboxylate.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The definitions for the terms described below are applicable to the useof the term by itself or in combination with another term.

The term “acyl” is art-recognized and refers to a group represented bythe general formula hydrocarbyl-C(O)—, preferably alkyl-C(O)—.

The term “acylamino” is art-recognized and refers to an amino groupsubstituted with an acyl group and may be represented, for example, bythe formula hydrocarbyl-C(O)NH—.

The term “acyloxy” is art-recognized and refers to a group representedby the general formula hydrocarbylC(O)O—, preferably alkylC(O)O—.

The term “alkoxy” refers to an alkyl group, preferably a lower alkylgroup, having an oxygen attached thereto. Representative alkoxy groupsinclude methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with analkoxy group and may be represented by the general formulaalkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic groupcontaining at least one double bond that is straight chained or branchedand has from 1 to about 20 carbon atoms, preferably from 1 to about 10unless otherwise defined. The term “alkenyl” is intended to include both“unsubstituted alkenyls” and “substituted alkenyls”, the latter of whichrefers to alkenyl moieties having substituents replacing a hydrogen onone or more carbons of the alkenyl group. Such substituents may occur onone or more carbons that are included or not included in one or moredouble bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed below, except where stability isprohibitive. For example, substitution of alkenyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

An “alkyl” group or “alkane” is a straight chained or branchednon-aromatic hydrocarbon which is completely saturated. Typically, astraight chained or branched alkyl group has from 1 to about 20 carbonatoms, preferably from 1 to about 10 unless otherwise defined. Examplesof straight chained and branched alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl,pentyl and octyl. A C₁-C₆ straight chained or branched alkyl group isalso referred to as a “lower alkyl” group.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification, examples, and claims is intended to include both“unsubstituted alkyls” and “substituted alkyls”, the latter of whichrefers to alkyl moieties having substituents replacing a hydrogen on oneor more carbons of the hydrocarbon backbone. Such substituents, if nototherwise specified, can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Itwill be understood by those skilled in the art that the moietiessubstituted on the hydrocarbon chain can themselves be substituted, ifappropriate. For instance, the substituents of a substituted alkyl mayinclude substituted and unsubstituted forms of amino, azido, imino,amido, phosphoryl (including phosphonate and phosphinate), sulfonyl(including sulfate, sulfonamido, sulfamoyl and sulfonate), and silylgroups, as well as ethers, alkylthiols, carbonyls (including ketones,aldehydes, carboxylates, and esters), —CF₃, —CN and the like. Exemplarysubstituted alkyls are described below. Cycloalkyls can be furthersubstituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls,carbonyl-substituted alkyls, —CF₃, —CN, and the like.

The term “C_(x-y)” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups that contain from x to y carbons in the chain. Forexample, the term “C_(x-y)alkyl” refers to substituted or unsubstitutedsaturated hydrocarbon groups, including straight-chain alkyl andbranched-chain alkyl groups that contain from x to y carbons in thechain, including haloalkyl groups such as trifluoromethyl and2,2,2-tirfluoroethyl, etc. C₀ alkyl indicates a hydrogen where the groupis in a terminal position, a bond if internal. The terms“C_(2-y)alkenyl” and “C_(2-y)alkynyl” refer to substituted orunsubstituted unsaturated aliphatic groups analogous in length andpossible substitution to the alkyls described above, but that contain atleast one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino groupsubstituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol groupsubstituted with an alkyl group and may be represented by the generalformula alkyl-S—.

The term “alkynyl”, as used herein, refers to an aliphatic groupcontaining at least one triple bond and is intended to include both“unsubstituted alkynyls” and “substituted alkynyls”, the latter of whichrefers to alkynyl moieties having substituents replacing a hydrogen onone or more carbons of the alkynyl group. Such substituents may occur onone or more carbons that are included or not included in one or moretriple bonds. Moreover, such substituents include all those contemplatedfor alkyl groups, as discussed above, except where stability isprohibitive. For example, substitution of alkynyl groups by one or morealkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups iscontemplated.

The term “amide”, as used herein, refers to a group

wherein each R¹⁰ independently represent a hydrogen or hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines and salts thereof, e.g., a moietythat can be represented by

wherein each R¹⁰ independently represents a hydrogen or a hydrocarbylgroup, or two R¹⁰ are taken together with the N atom to which they areattached complete a heterocycle having from 4 to 8 atoms in the ringstructure.

The term “aminoalkyl”, as used herein, refers to an alkyl groupsubstituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group. An aralkyl group is connected to the rest of themolecule through the alkyl component of the aralkyl group.

The term “aryl” as used herein include substituted or unsubstitutedsingle-ring aromatic groups in which each atom of the ring is carbon.Preferably the ring is a 5- to 10-membered ring, more preferably a 6- to10-membered ring or a 6-membered ring. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline,and the like. Exemplary substitution on an aryl group can include, forexample, a halogen, a haloalkyl such as trifluoromethyl, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acylsuch as an alkylC(O)), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, aphosphonate, a phosphinate, an amino, an amido, an amidine, an imine, acyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety

The term “carbamate” is art-recognized and refers to a group

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbylgroup, such as an alkyl group, or R⁹ and R¹⁰ taken together with theintervening atom(s) complete a heterocycle having from 4 to 8 atoms inthe ring structure.

The terms “carbocycle”, and “carbocyclic”, as used herein, refers to asaturated or unsaturated ring in which each atom of the ring is carbon.The term carbocycle includes both aromatic carbocycles and non-aromaticcarbocycles. Non-aromatic carbocycles include both cycloalkane rings, inwhich all carbon atoms are saturated, and cycloalkene rings, whichcontain at least one double bond. “Carbocycle” includes 5-7 memberedmonocyclic and 8-12 membered bicyclic rings. Each ring of a bicycliccarbocycle may be selected from saturated, unsaturated and aromaticrings. Carbocycle includes bicyclic molecules in which one, two or threeor more atoms are shared between the two rings. The term “fusedcarbocycle” refers to a bicyclic carbocycle in which each of the ringsshares two adjacent atoms with the other ring. Each ring of a fusedcarbocycle may be selected from saturated, unsaturated and aromaticrings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, maybe fused to a saturated or unsaturated ring, e.g., cyclohexane,cyclopentane, or cyclohexene. Any combination of saturated, unsaturatedand aromatic bicyclic rings, as valence permits, is included in thedefinition of carbocyclic. Exemplary “carbocycles” include cyclopentane,cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene andadamantane. Exemplary fused carbocycles include decalin, naphthalene,1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane,4,5,6,7-tetrahydro-1H-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles”may be substituted at any one or more positions capable of bearing ahydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completelysaturated. “Cycloalkyl” includes monocyclic and bicyclic rings.Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbonatoms, more typically 3 to 8 carbon atoms unless otherwise defined. Thesecond ring of a bicyclic cycloalkyl may be selected from saturated,unsaturated and aromatic rings. Cycloalkyl includes bicyclic moleculesin which one, two or three or more atoms are shared between the tworings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl inwhich each of the rings shares two adjacent atoms with the other ring.The second ring of a fused bicyclic cycloalkyl may be selected fromsaturated, unsaturated and aromatic rings. A “cycloalkenyl” group is acyclic hydrocarbon containing one or more double bonds.

The term “cycloalkylalkyl”, as used herein, refers to an alkyl groupsubstituted with a cycloalkyl group.

The term “carbonate” is art-recognized and refers to a group —OCO2-R¹⁰,wherein R¹⁰ represents a hydrocarbyl group.

The term “carboxyl”, as used herein, refers to a group represented bythe formula —CO₂H.

The term “ester”, as used herein, refers to a group —C(O)OR¹⁰ whereinR¹⁰ represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linkedthrough an oxygen to another hydrocarbyl group. Accordingly, an ethersubstituent of a hydrocarbyl group may be hydrocarbyl-O—. Ethers may beeither symmetrical or unsymmetrical. Examples of ethers include, but arenot limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethersinclude “alkoxyalkyl” groups, which may be represented by the generalformula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means halogen and includeschloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group.

The term “heteroalkyl”, as used herein, refers to a saturated orunsaturated chain of carbon atoms and at least one heteroatom, whereinno two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted orunsubstituted aromatic single ring structures, preferably 5- to7-membered rings, more preferably 5- to 6-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems havingtwo or more cyclic rings in which two or more carbons are common to twoadjoining rings wherein at least one of the rings is heteroaromatic,e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroarylgroups include 5- to 10-membered cyclic or polycyclic ring systems,including, for example, pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, andthe like. Exemplary optional substituents on heteroaryl groups includethose substituents put forth as exemplary substituents on aryl groups,above.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, andsulfur.

The terms “heterocycloalkyl”, “heterocycle”, and “heterocyclic” refer tosubstituted or unsubstituted non-aromatic ring structures, preferably 3-to 10-membered rings, more preferably 3- to 7-membered rings, whose ringstructures include at least one heteroatom, preferably one to fourheteroatoms, more preferably one or two heteroatoms. The terms“heterocycloalkyl” and “heterocyclic” also include polycyclic ringsystems having two or more cyclic rings in which two or more carbons arecommon to two adjoining rings wherein at least one of the rings isheterocyclic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/orheterocycloalkyls. Heterocycloalkyl groups include, for example,piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, andthe like.

The term “heterocycloalkylalkyl”, as used herein, refers to an alkylgroup substituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bondedthrough a carbon atom that does not have a ═O or ═S substituent, andtypically has at least one carbon-hydrogen bond and a primarily carbonbackbone, but may optionally include heteroatoms. Thus, groups likemethyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to behydrocarbyl for the purposes of this application, but substituents suchas acetyl (which has a ═O substituent on the linking carbon) and ethoxy(which is linked through oxygen, not carbon) are not. Hydrocarbyl groupsinclude, but are not limited to aryl, heteroaryl, carbocycle,heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term “hydroxyalkyl”, as used herein, refers to an alkyl groupsubstituted with a hydroxy group.

The term “lower” when used in conjunction with a chemical moiety, suchas, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant toinclude groups where there are ten or fewer non-hydrogen atoms in thesubstituent, preferably six or fewer. A “lower alkyl”, for example,refers to an alkyl group that contains ten or fewer carbon atoms,preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl,alkenyl, alkynyl, or alkoxy substituents defined herein are respectivelylower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, orlower alkoxy, whether they appear alone or in combination with othersubstituents, such as in the recitations hydroxyalkyl and aralkyl (inwhich case, for example, the atoms within the aryl group are not countedwhen counting the carbon atoms in the alkyl substituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two ormore rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls) in which two or more atoms are commonto two adjoining rings, e.g., the rings are “fused rings”. Each of therings of the polycycle can be substituted or unsubstituted. In certainembodiments, each ring of the polycycle contains from 3 to 10 atoms inthe ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbylmoieties attached thereto. A “silyl ether” refers to a silyl grouplinked through an oxygen to a hydrocarbyl group. Exemplary silyl ethersinclude —OSi(CH₃)₃ (—OTMS), —OSi(CH₃)₂t-Bu (—OTBS), —OSi(Ph)₂t-Bu(—OTBDPS), and —OSi(iPr)₃ (—OTIPS).

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons of the backbone. It will be understoodthat “substitution” or “substituted with” includes the implicit provisothat such substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and non-aromaticsubstituents of organic compounds. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this invention, the heteroatoms such as nitrogen mayhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. Substituents can include any substituents described herein,for example, a halogen, a haloalkyl, a hydroxyl, a carbonyl (such as acarboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (suchas a thioester, a thioacetate, or a thioformate), an alkoxyl, aphosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, anamido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl,an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, asulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromaticmoiety. It will be understood by those skilled in the art thatsubstituents can themselves be substituted, if appropriate. Unlessspecifically stated as “unsubstituted,” references to chemical moietiesherein are understood to include substituted variants. For example,reference to an “aryl” group or moiety implicitly includes bothsubstituted and unsubstituted variants.

The term “sulfate” is art-recognized and refers to the group —OSO3H, ora pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art-recognized and refers to the grouprepresented by the general formulae

wherein R⁹ and R¹⁰ independently represents hydrogen or hydrocarbyl,such as alkyl, or R⁹ and R¹⁰ taken together with the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art-recognized and refers to the group—S(O)—R¹⁰, wherein R¹⁰ represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO₃H, ora pharmaceutically acceptable salt thereof. In some embodiments, asulfonate can mean an alkylated sulfonate of the formula SO₃(alkyl).

The term “sulfone” is art-recognized and refers to the group —S(O)₂—R¹⁰,wherein R¹⁰ represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl groupsubstituted with a thiol group.

The term “thioester”, as used herein, refers to a group —C(O)SR¹⁰ or—SC(O)R¹⁰ wherein R¹⁰ represents a hydrocarbyl.

The term “thioether”, as used herein, is equivalent to an ether, whereinthe oxygen is replaced with a sulfur.

The term “urea” is art-recognized and may be represented by the generalformula

wherein R⁹ and R¹⁰ independently represent hydrogen or a hydrocarbyl,such as alkyl, or either occurrence of R⁹ taken together with R¹⁰ andthe intervening atom(s) complete a heterocycle having from 4 to 8 atomsin the ring structure.

“Protecting group” refers to a group of atoms that, when attached to areactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group may beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts,Protective Groups in Organic Chemistry, 3^(rd)Ed., 1999, John Wiley &Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods,Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogenprotecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“TES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxyl protecting groupsinclude, but are not limited to, those where the hydroxyl group iseither acylated (esterified) or alkylated such as benzyl and tritylethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers (e.g., TMS or TIPS groups), glycol ethers, such as ethyleneglycol and propylene glycol derivatives and allyl ethers.

II. Description of the Invention

This invention is based on the discovery of an efficient, scalablecatalytic decarboxylative allylic alkylation reaction that generatescyclic cycloalkanone and lactam products having an α-stereocenter, suchas lactones, thiolactones, cycloalkanones, and lactams. Thedecarboxylative allylic alkylation reaction is catalyzed by a robustPd(II) catalyst and a ligand, preferably a chiral ligand, and theproducts can be quickly and efficiently elaborated into complexproducts.

According to embodiments of the present invention, a wide range ofstructurally-diverse, functionalized products are prepared by a readilyscalable stereoselective method of palladium-catalyzed enantioselectiveenolate allylic alkylation. This chemistry is useful in the synthesis ofbioactive alkaloids, and for the construction of novel building blocksfor medicinal and polymer chemistry.

Indeed, in some embodiments of the present invention, a method of makinga building block compound comprises reacting a substrate compound with aligand in the presence of a palladium-based catalyst and a solvent. Thepalladium-based catalysts, ligands and solvents useful in this reactionare described in more detail below in Section III.

III. Methods of the Invention

In certain aspects, the present invention provides a method forpreparing a compound of formula (I):

comprising treating a compound of formula (II) or (III):

or a salt thereof;

-   with a Pd(II) catalyst under alkylation conditions, wherein, as    valence and stability permit,-   R¹ represents hydrogen or substituted or unsubstituted alkyl,    alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,    (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkoxy, amino, or halo;-   R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selected    for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl,    alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy,    alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    thioalkyl, ether, thioether, ester, amide, thioester, carbonate,    carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl,    acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,    aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and    (heterocycloalkyl)alkyl;-   W represents, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—, —C(O)—,    —CR⁷═, or —N═;-   R⁶ represents hydrogen or optionally substituted alkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,    alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,    —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl),    —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl),    —S(O)₂(aryl), —S(O)₂(alkyl), —S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or    —NR¹⁰R¹¹;-   R⁷ and R⁸ each independently represent hydrogen, hydroxyl, halogen,    nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,    heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl,    heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino,    alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl,    alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether,    ester, amido, thioester, carbonate, carbamate, urea, sulfonate,    sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;-   or R⁶, R⁷, and R⁸ taken together with a substituent on ring A and    the intervening atoms, form an optionally substituted aryl,    heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or    heterocycloalkenyl group;-   R¹⁰ and R¹¹ are independently selected for each occurrence from    hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl,    heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl,    (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl; and-   ring A represents an optionally substituted cycloalkyl,    heterocycloalkyl, cycloalkenyl, or heterocycloalkenyl group.

In certain embodiments, the compound of formula (I) is represented byformula (Ia):

andthe compound of formula (II) is represented by formula (IIa):

andthe compound of formula (III) is represented by formula (IIIa):

-   In certain such embodiments, B, D, and E each independently for each    occurrence represent, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—,    —C(O)—, —CR⁷═, or —N═; provided that no two adjacent occurrences of    W, B, D, and E are NR⁶, O, S, or N;-   or any two occurrences of R⁶, R⁷, and R⁸ on adjacent W, B, D, or E    groups, taken together with the intervening atoms, form an    optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl,    heterocycloalkyl, or heterocycloalkenyl group;-   each occurrence of    independently represents a double bond or a single bond as permitted    by valence; and-   m and n are integers each independently selected from 0, 1, and 2.

In certain embodiments, W represents —O—, —S—, —NR⁶—, —CR⁷R⁸— or —CR⁷═.

In certain embodiments, the sum of m and n is 0, 1, 2, or 3; that is,ring A is a 4-7 membered ring.

In certain embodiments, ring A is a carbocyclic ring.

In certain such embodiments, each occurrence of W, B, D, and E isindependently —CR⁷R⁸—, or —CR⁷—, or —C(O)—. For example, one occurrenceof W, B, D, and E may be —CR⁷R⁸— or —C(O)—, while the remaining threemay be —CR⁷R⁸—. In certain such embodiments, R⁷ and R⁸, independentlyfor each occurrence, are selected from hydrogen, hydroxyl, halogen,alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl,alkynyl, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, and amido.

In certain embodiments, ring A contains one or more double bonds, e.g.,one or more carbon-carbon double bonds.

In certain such embodiments, at least two adjacent occurrences of W, B,D, and E are —CR⁷—. For example, W and B may each be —CR⁷— while m is 1.In certain such embodiments, R⁷ is independently selected for eachoccurrence from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,(heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino,alkoxy, aryloxy, alkylamino, amido, and acylamino; or the occurrence ofR⁷ on W and the occurrence of R⁷ on B are taken together to form anoptionally substituted aryl, heteroaryl, cycloalkenyl, orheterocycloalkenyl group. In further such embodiments, the occurrence ofR⁷ on W and the occurrence of R⁷ on B are taken together to form anoptionally substituted aryl, heteroaryl, cycloalkenyl, orheterocycloalkenyl group, preferably an optionally substituted arylgroup. For example, ring A may be a tetralone-derived substrate.

Alternatively, in certain embodiments in which W and B are each —CR⁷—,the occurrence of R⁷ on W is selected from amino, alkylamino, amido,acylamino, and N-bound heterocycloalkyl.

In alternative embodiments, at least one occurrence of W, B, D, and E is—NR⁶—. For example, W may be —NR⁶—. In certain such embodiments, atleast one occurrence of the remaining B, D, and E is —NR⁶— or —O—. Infurther such embodiments, R⁶ represents, independently for eachoccurrence, hydrogen or optionally substituted alkyl, aralkyl,heteroaralkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl).

In certain embodiments, at least one occurrence of W, B, D, and E is—O—.

In certain embodiments, R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are eachindependently selected for each occurrence from hydrogen, halogen,cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and arylalkoxy.For example, R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are eachindependently hydrogen or lower alkyl. Preferably, R², R³, R⁴, R⁵, R¹²,R¹³, R¹⁴, and R¹⁵ are each hydrogen.

In certain embodiments, R¹ represents substituted or unsubstitutedalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl,heterocycloalkyl, or halo.

In certain embodiments, R¹ represents substituted or unsubstitutedalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl,(cycloalkyl)alkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, or halo.In certain such embodiments, R¹ is selected from optionally substitutedalkyl, aryl, aralkyl, haloalkyl, alkoxyalkyl, and hydroxyalkyl. Forexample, R¹ may be alkyl, optionally substituted with halo, hydroxy,alkoxy, aryloxy, arylalkoxy, cyano, nitro, azido, —CO₂H, —C(O)O(alkyl),amino, alkylamino, arylamino, aralkylamino, and amido.

In certain embodiments, the method for preparing a compound of formula(I) comprises treating a compound of formula (II) with a Pd(II) catalystunder alkylation conditions.

In certain embodiments, the method for preparing a compound of formula(I) comprises treating a compound of formula (III) with a Pd(II)catalyst under alkylation conditions.

In certain embodiments, the method yields a compound of formula (I) thatis enantioenriched.

In further aspects, the present invention provides a method forpreparing a compound of formula (I), described above, comprisingtreating a compound of formula (IV) or (V) or a salt thereof:

-   -   with a compound of formula (X):

and

-   a Pd(II) catalyst under alkylation conditions, wherein, as valence    and stability permit,-   W, R¹, R¹², R¹³, R¹⁴, R¹⁵, and ring A are as defined for    formulae (I) and (II), above; and further wherein:-   R^(a) represents optionally substituted alkyl, aryl, or alkoxyl; and-   X represents a halide, carbonate, sulfonate, acetate, or    carboxylate.

In certain embodiments, the compound of formula (I) is represented byformula (Ia):

andthe compound of formula (IV) is represented by formula (IVa):

andthe compound of formula (V) is represented by formula (Va):

wherein substituents B, D, E, n, and m are defined above for formulae(Ia), (IIa), and (IIIa).

In certain embodiments, the alkylation conditions under which thecompound of formula (IV) or (V) reacts to form a compound of formula (I)further comprise a fluoride source, such as TBAT, TBAF, LiBF₄, or atetraalkylammonium fluoride salt.

In certain embodiments, the method for preparing a compound of formula(I) comprises treating a compound of formula (IV) with a Pd(II) catalystunder alkylation conditions.

In certain embodiments, the method for preparing a compound of formula(I) comprises treating a compound of formula (V) with a Pd(II) catalystunder alkylation conditions.

Transition Metal Catalysts

Preferred transition metal catalysts of the invention are complexes ofpalladium (II).

It should be appreciated that typical transition metal catalysts havinga low oxidation state (e.g., (0) or (I)) suffer from air- andmoisture-sensitivity, such that these complexes of transition metalsnecessitate appropriate handling precautions. This may include thefollowing precautions without limitation: minimizing exposure of thereactants to air and water prior to reaction; maintaining an inertatmosphere within the reaction vessel; properly purifying all reagents;and removing water from reaction vessels prior to use.

Palladium (II) catalysts are typically robust, and are less sensitive toair and moisture than their lower-oxidation state counterparts.

Exemplary Pd (II) catalysts that may be used in the methods of theinvention include Pd(OC(O)R^(c))₂, wherein R^(c) is optionallysubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl, heterocycloalkyl, (cycloalkyl)alkyl, or(heterocycloalkyl)alkyl. Further exemplary Pd (II) catalysts includePd(OC(O)R^(c))₂, Pd(OC(═O)CH₃)₂ (i.e., Pd(OAc)₂), Pd(TFA)₂, Pd(acac)₂,PdCl₂, PdBr₂, PdCl₂(R²³CN)₂ (e.g., Pd(PhCN)₂C₁₂ and Pd(CH₃CN)₂Cl₂),PdCl₂(PR²⁴R²⁵R²⁶)₂, [Pd(η³-allyl)Cl]₂, and pre-formed Pd(II)-ligandcomplex, wherein R²³, R²⁴, R²⁵, and R²⁶ are independently selected fromhydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl,and substituted heteroatom-containing hydrocarbyl. In preferredembodiments, the transition metal catalyst is Pd(OAc)₂. Alternatively,the transition metal catalyst is Pd(OC(O)R^(c))₂, wherein R^(c) isdefined above. For example, R^(c) may be alkyl, substituted by one ormore halo or cyano groups.

To improve the effectiveness of the catalysts discussed herein,additional reagents may be employed, including, without limitation,salts, solvents, and other small molecules. Preferred additives includeAgBF₄, AgOSO₂CF₃, AgOC(═O)CH₃, and bipyridine. These additives arepreferably used in an amount that is in the range of about 1 equivalentto about 5 equivalents relative to the amount of the catalyst.

A low oxidation state of a transition metal, i.e., an oxidation statesufficiently low to undergo oxidative addition, can be obtained in situ,by the reduction of transition metal complexes that have a highoxidation state. Reduction of the transition metal complex canoptionally be achieved by adding nucleophilic reagents including,without limitation, tetrabutylammonium hydroxide, tetrabutylammoniumdifluorotriphenylsilicate (TBAT), tetrabutylammonium fluoride (TBAF),4-dimethylaminopyridine (DMAP), tetramethylammonium hydroxide (e.g., asthe pentahydrate), KOH/1,4,7,10,13,16-hexaoxacyclooctadecane, sodiumethoxide, TBAT/trimethyl-(2-methyl-cyclohex-1-enyloxy)-silane, andcombinations thereof. When a nucleophilic reagent is needed for thereduction of the metal complex, the nucleophilic reagent is used in anamount in the range of about 1 mol % to about 20 mol % relative to thereactant, more preferably in the range of about 1 mol % to about 10 mol% relative to the substrate, and most preferably in the range of about 5mol % to about 8 mol % relative to the substrate.

For example, a Pd(II) complex can be reduced in situ to form a Pd(0)catalyst. Exemplary transition metal complexes that may be reduced insitu, include, without limitation,allylchloro[1,3-bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]palladium(II),([2S,3S]-bis[diphenylphosphino]butane)(η³-allyl)palladium(II)perchlorate,[S]-4-tert-butyl-2-(2-diphenylphosphanyl-phenyl)-4,5-dihydro-oxazole(η³-allyl)palladium(II)hexafluorophosphate (i.e., [Pd(S-tBu-PHOX)(allyl)]PF₆), andcyclopentadienyl(η³-allyl) palladium(II).

Accordingly, when describing the amount of transition metal catalystused in the methods of the invention, the following terminology applies.The amount of transition metal catalyst present in a reaction isalternatively referred to herein as “catalyst loading”. Catalyst loadingmay be expressed as a percentage that is calculated by dividing themoles of catalyst complex by the moles of the substrate present in agiven reaction. Catalyst loading is alternatively expressed as apercentage that is calculated by dividing the moles of total transitionmetal (for example, palladium) by the moles of the substrate present ina given reaction.

In certain embodiments, the transition metal catalyst is present underthe conditions of the reaction from an amount of about 0.01 mol % toabout 10 mol % total palladium relative to the substrate, which is thecompound of formula (II), (III), (IV), or (V). In certain embodiments,the catalyst loading is from about 0.05 mol % to about 5 mol % totalpalladium relative to the substrate. In certain embodiments, thecatalyst loading is from about 0.05 mol % to about 2.5 mol %, about 0.05mol % to about 2%, about 0.05 mol % to about 1%, about 0.02 mol % toabout 5 mol %, about 0.02 mol % to about 2.5 mol %, about 0.02 mol % toabout 1 mol %, about 0.1 mol % to about 5 mol %, about 0.1 mol % toabout 2.5 mol %, or about 0.1 mol % to about 1 mol % total palladiumrelative to the substrate. For example, in certain embodiments, thecatalyst loading is about 0.01 mol %, about 0.05 mol %, about 0.1 mol %,about 0.15 mol %, about 0.2 mol %, about 0.25 mol %, about 0.3 mol %,about 0.4 mol %, about 0.5 mol %, about 0.6 mol %, about 0.7 mol %,about 0.8 mol %, about 0.9 mol %, about 1 mol %, about 1.5 mol %, about2 mol %, about 3 mol %, or about 5 mol % total palladium.

Ligands

One aspect of the invention relates to the enantioselectivity of themethods. Enantioselectivity results from the use of chiral ligandsduring the allylic alkylation reaction. Accordingly, in certainembodiments, the Pd (II) catalyst further comprises a chiral ligand.Without being bound by theory, the asymmetric environment that iscreated around the metal center by the presence of chiral ligandsproduces an enantioselective reaction. The chiral ligand forms a complexwith the transition metal (i.e., palladium), thereby occupying one ormore of the coordination sites on the metal and creating an asymmetricenvironment around the metal center. This complexation may or may notinvolve the displacement of achiral ligands already complexed to themetal. When displacement of one or more achiral ligands occurs, thedisplacement may proceed in a concerted fashion, i.e., with both theachiral ligand decomplexing from the metal and the chiral ligandcomplexing to the metal in a single step. Alternatively, thedisplacement may proceed in a stepwise fashion, i.e., with decomplexingof the achiral ligand and complexing of the chiral ligand occurring indistinct steps. Complexation of the chiral ligand to the transitionmetal may be allowed to occur in situ, i.e., by admixing the ligand andmetal before adding the substrate. Alternatively, the ligand-metalcomplex can be formed separately, and the complex isolated before use inthe alkylation reactions of the present invention.

Once coordinated to the transition metal center, the chiral ligandinfluences the orientation of other molecules as they interact with thetransition metal catalyst. Coordination of the metal center with aπ-allyl group and reaction of the substrate with the π-allyl-metalcomplex are dictated by the presence of the chiral ligand. Theorientation of the reacting species determines the stereochemistry ofthe products.

Chiral ligands of the invention may be bidentate or monodentate or,alternatively, ligands with higher denticity (e.g., tridentate,tetradentate, etc.) can be used. Preferably, the ligand will besubstantially enantiopure. By “enantiopure” is meant that only a singleenantiomer is present. In many cases, substantially enantiopure ligands(e.g., ee>99%, preferably >99.5%, even more preferably >99.9%) can bepurchased from commercial sources, obtained by successiverecrystallizations of an enantioenriched substance, or by other suitablemeans for separating enantiomers.

Exemplary chiral ligands may be found in U.S. Pat. No. 7,235,698, theentirety of which is incorporated herein by reference. In certainembodiments, the chiral ligand is an enantioenriched phosphine ligand.In certain embodiments, the enantioenriched phosphine ligand is aP,N-ligand such as a phosphinooxazoline (PHOX) ligand. Preferred chiralligands of the invention include the PHOX-type chiral ligands such as(R)-2-[2-(diphenylphosphino)phenyl]-4-isopropyl-2-oxazoline,(R)-2-[2-(diphenylphosphino)phenyl]-4-phenyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-benzyl-2-oxazoline,(S)-2-[2-(diphenylphosphino)phenyl]-4-tert-butyl-2-oxazoline((S)-t-BuPHOX) and(S)-2-(2-(bis(4-(Trifluoromethyl)phenyl)phosphino)-5-(trifluoromethyl)phenyl)-4-(tert-butyl)-4,5-dihydrooxazole((S)—(CF₃)₃-t-BuPHOX). In preferred embodiments, the PHOX type chiralligand is selected from (S)-t-BuPHOX and (S)—(CF₃)₃-t-BuPHOX). Theligand structures are depicted below.

Generally, the chiral ligand is present in an amount in the range ofabout 1 equivalents to about 20 equivalents relative to the amount oftotal metal from the catalyst, preferably in the range of about 5 toabout 15 equivalents relative to the amount of total metal from thecatalyst, and most preferably in the range of about 10 equivalentsrelative to the amount of total metal from the catalyst. Alternatively,the amount of the chiral ligand can be measured relative to the amountof the substrate.

In certain embodiments, the ligand is present under the conditions ofthe reaction from an amount of about 0.1 mol % to about 100 mol %relative to the substrate, which is the compound of formula (II), (III),(IV), or (V). The amount of ligand present in the reaction isalternatively referred to herein as “ligand loading” and is expressed asa percentage that is calculated by dividing the moles of ligand by themoles of the substrate present in a given reaction. In certainembodiments, the ligand loading is from about 0.5 mol % to about 50 mol%. For example, in certain embodiments, the ligand loading is aboutabout 1 mol %, about 1.5 mol %, about 2 mol %, about 2.5 mol %, about 3mol %, about 4 mol %, or about 5 mol %. In certain embodiments, theligand is in excess of the transition metal catalyst. In certainembodiments, the ligand loading is about 10 times the transition metalcatalyst loading. Without being bound to theory, it is thought that theligand (e.g., the PHOX ligand) may act as the reductive agent thatgenerates Pd(0) in situ.

Where a chiral ligand is used, the reactions of the invention may enrichthe stereocenter bearing R¹ in the product relative to the enrichment atthis center, if any, of the starting material. In certain embodiments,the chiral ligand used in the methods of the invention yields a compoundof formula (I) that is enantioenriched. The level of enantioenrichmentof a compound may be expressed as enantiomeric excess (ee). The ee of acompound may be measured by dividing the difference in the fractions ofthe enantiomers by the sum of the fractions of the enantiomers. Forexample, if a compound is found to comprise 98% (S)-enantiomer, and 2%(R) enantiomer, then the ee of the compound is (98−2)/(98+2), or 96%. Incertain embodiments, the compound of formula (I) has about 30% ee orgreater, 40% ee or greater, 50% ee or greater, 60% ee or greater, 70% eeor greater, about 80% ee, about 85% ee, about 88% ee, about 90% ee,about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee,about 96% ee, about 97% ee, about 98% ee, about 99% ee, or above about99% ee, even where this % ee is greater than the % ee of the startingmaterial, such as 0%/a ee (racemic). In certain embodiments, thecompound of formula (I) is enantioenriched. In certain embodiments, thecompound of formula (I) is enantiopure. In embodiments where thestarting material has more than one stereocenter, reactions of theinvention may enrich the stereocenter bearing R¹ relative to theenrichment at this center, if any, of the starting material, andsubstantially independently of the stereochemical disposition/enrichmentof any other stereocenters of the molecule. For example, a product ofthe methods described herein may have 30% de or greater, 40% de orgreater, 50% de or greater, 60% de or greater, 70% de or greater, 80% deor greater, 90% de or greater, 95% de or greater, or even 98% de orgreater at the stereocenter of the product bearing R¹.

In certain embodiments, the invention also relates to methods thatutilize an achiral ligand. Exemplary achiral ligands includetriphenylphosphine, tricyclohexylphosphine, tri-(ortho-tolyl)phosphine,trimethylphosphite, and triphenylphosphite.

Alkylation Conditions

In certain embodiments, the methods of the invention include treating acompound of formula (II), (III), (IV), or (V) with a Pd (II) catalystunder alkylation conditions. In certain embodiments, alkylationconditions of the reaction include one or more organic solvents. Incertain embodiments, organic solvents include aromatic or non-aromatichydrocarbons, ethers, alkylacetates, nitriles, or combinations thereof.In certain embodiments, organic solvents include hexane, pentane,benzene, toluene, xylene, cyclic ethers such as optionally substitutedtetrahydrofuran and dioxane, acyclic ethers such as dimethoxyethane,diethyl ether, methyl tertbutyl ether, and cyclopentyl methyl ether,acetonitrile, isobutyl acetate, ethyl acetate, isopropyl acetate, orcombinations thereof. In certain preferred embodiments, the solvent istoluene, methyl tertbutyl ether, or 2-methyltetrahydrofuran. In certainother preferred embodiments, the solvent is methyl tertbutyl ether.

In certain embodiments, alkylation conditions of the reaction include areaction temperature. In certain embodiments, the reaction temperatureis ambient temperature (about 20° C. to about 26° C.). In certainembodiments, the reaction temperature is higher than ambienttemperature, such as, for example, about 30° C., about 35° C., about 40°C., about 45° C., about 50° C., about 55° C., or about 60° C. Reactiontemperature may be optimized per each substrate.

In certain embodiments, instruments such as a microwave reactor may beused to accelerate the reaction time. Pressures range from atmosphericto pressures typically used in conjunction with supercritical fluids,with the preferred pressure being atmospheric.

EXEMPLIFICATION

The invention described generally herein will be more readily understoodby reference to the following examples, which are included merely forpurposes of illustration of certain aspects and embodiments of thepresent invention, and are not intended to limit the invention.

Example 1. Exploration of Alternative Pd-Catalyst

Pd₂(dba)₃ is known to be oxygen-sensitive. In order to increase thescalability of the reaction, alternative Pd-based catalysts wereexplored. The catalytic cycle of the allylic alkylation operatesstarting from a zero valent palladium source and is believed to involvea palladium (0/II) redox cycle.^([6]) While utilization of Pd₂(dba)₃renders in situ reduction of the catalyst obsolete, its application ishampered by increased sensitivity to oxygen. Furthermore, thedibenzylideneacetone ligand is challenging to separate from non-polarreaction products. Below is a survey of a variety of Pd(II) sources incombination with the chiral phosphinooxazoline ligands (S)-t-BuPHOX3^([7]) and (S)—(CF₃)₃-t-BuPHOX 4.^([8])

TABLE 1 Comparison between palladium precursors in different oxidationstates.

Ligand Pd Entry [mmol] source [mol %] Pd Yield [%] ^(a)) ee [%] ^(b)) 13 10.0 Pd(OAc)₂ 1.0 99 86 2 4 10.0 Pd(OAc)₂ 1.0 99 82 3 3 10.0 Pd₂(dba)₃1.0 99 84 4 4 10.0 Pd₂(dba)₃ 1.0 90 82 5 3 1.0 Pd(OAc)₂ 0.1 99 79 6 41.0 Pd(OAc)₂ 0.1 99 83 7 3 1.0 Pd₂(dba)₃ 0.1 12 n.d. 8 4 1.0 Pd₂(dba)₃0.1 14 n.d. ^(a)) GC yield relative to an internal standard (tridecane).^(b)) Enantiomeric excess measured by chiral GC.

When comparing Pd(OAc)₂ and Pd₂(dba)₃ at 1.0 mol % palladium incombination with a tenfold excess of PHOX ligands 3 or 4 respectively,in TBME at 80° C. both palladium sources exhibited comparable catalyticperformance (Table 1, entries 1-4). At lower palladium concentrations,however, Pd(OAc)₂ was clearly superior, delivering quantitative yieldsand good enantioselectivity at only 0.10 mol % Pd (Table 1, entries 5and 6). When 0.10 mol % Pd₂(dba)₃ was used to form the catalyst, adramatic decrease in yields was observed (Table 1, entries 7 and 8).

Other palladium(II) sources were then investigated to determine whetherthe sources were equally suited to catalyze the decarboxylative allylicalkylation. Consequently, a total of eight different commerciallyavailable Pd(II) precursors were examined in our model reaction in thepresence of ligand 3 (Pd(OAc)₂, PdCl₂, Pd(PhCN)₂Cl₂, Pd(CH₃CN)₂Cl₂,PdBr₂, Pd(acac)₂, [Pd(allyl)Cl]₂, Pd(TFA)₂). Solubility of certainpalladium salts in TBME can hinder catalysis.

Example 2. Exploration of Catalyst Loading

Using Pd(OAc)₂ as the palladium catalyst precursor, we turned ourattention to minimizing the catalyst loading. A screening of sixdifferent catalyst loadings, ranging from 0.05 mol % to 1.0 mol %, wasperformed (Table 2). All reactions were conducted in the presence of atenfold excess of ligand with respect to palladium, in TBME at 40° C.The high-excess of ligand was chosen to facilitate formation of theactive catalyst through in situ reduction of Pd(OAc)₂. We reasoned thatthe PHOX ligand hereby acts as the reductive agent.

Under these reaction conditions, palladium loadings as low as 0.10 mol %were sufficient to deliver the desired allylic alkylation product in 90%yield and with high enantioselectivity (Table 2, entry 5). To obtain aquantitative yield of ketone 2a, the catalyst loading was increased to0.15 mol % of Pd(OAc)₂ (Table 2, entry 4).

TABLE 2 Assessment of the Pd(OAc)₂ loading for the decarboxylativeallylic alkylation.

Entry Pd [mol %] 3 [mol %] Yield [%] ^(a)) ee [%] ^(b)) 1 1.00 10.0 9990 2 0.50 5.0 99 90 3 0.25 2.50 99 90 4 0.15 1.50 99 89 5 0.10 1.0 90 896 0.05 0.50 10 89 ^(a)) GC yield relative to an internal standard(tridecane). ^(b)) Enantiomeric excess measured by chiral GC.

Example 3. Solvent Survey

Enantioselective allylic alkylation reactions are typically performed insolvents such as THF, DCM, dioxane, or diethylether. While thesesolvents are common for academic laboratory scale, their use prohibitsconducting the reaction in an industrial setting. We sought to overcomethis limitation and performed a solvent survey with a total oftendifferent solvents that are considered to be safe, sustainable andcost-efficient (Table 3).^([9,10])

Conversion of allyl 1-methyl-2-oxocyclohexane-carboxylate (1a) in TBMEresulted in a high yield and good enantioselectivity (Table 3, entry 1).When the reaction was performed in various alkyl acetates the yieldsdropped dramatically, to 12%, 28% and 17% respectively (Table 3, entries2, 4 and 5). Similarly low yields were observed for reactions performedin acetonitrile, dimethylacetamide, 2-Me-THF, and acetone (Table 3,entries 3, 6, 8 and 10). Moderate conversion was found when the reactionwas performed in toluene (Table 3, entry 7). Consequently, all furtherexperiments were carried out in TBME.

TABLE 3 Assessment of the reaction medium.

Entry solvent Yield [%] ^(a)) ee [%] ^(b)) 1 TBME 88 89 2 EtOAc 12 ^(c))74 3 Acetonitrile trace — 4 Isopropyl acetate 28 64 5 Isobutyl acetate17 — 6 Dimethylacetamide trace — 7 Toluene 52 80 8 2-Me—THF 21 89 9t-AmylOH — ^(c)) — 10 Acetone 12 ^(c)) 47 ^(a)) GC yield relative to aninternal standard (tridecane). ^(b)) Enantiomeric excess measured bychiral GC. ^(c)) Reaction performed at 60° C.

Example 4. Temperature Survey

At this point, we considered that the palladium concentration could belowered further by performing the reaction at higher temperatures, andwe were interested in the influence of increased reaction temperature onstereoselectivity. All experiments were performed in TBME with a tenfoldexcess of ligand 3 (Table 4). A palladium loading as low as 0.075 mol %afforded ketone 2a in 99% yield when the reaction was performed at 80°C., which corresponds to a turnover number of 1320 for the in situformed catalyst. Nevertheless, a slightly lower enantioselectivity of84% was observed in this case (Table 4, entry 1). At 60 OC and 40° C.,palladium loadings of 0.10 and 0.125 mol % respectively were sufficientto deliver the desired product in quantitative yield and retain highenantioselectivity (Table 4, entries 2 and 3).

TABLE 4 Assessment of the palladium loading for the decarboxylativeallylic alkylation at various temperatures.

Entry Pd [mol %] T [° C.] Yield [%] ^(a)) ee [%] ^(b)) 1 0.075 80 99 842 0.10 60 99 88 3 0.125 40 99 89 ^(a)) GC yield relative to an internalstandard (tridecane). ^(b)) Enantiomeric excess measured by chiral GC.

Example 5. Increasing Reaction Scale

We then applied the protocol to the 10 and 20 mmol scale synthesis ofalpha-quaternary ketones 2a and 2b (Table 5). Both reactions wereperformed in TBME with a tenfold excess of ligand 3. Cyclohexanone 1awas converted on a 10.0 mmol scale (1.96 g) in the presence of 0.15 mol% (3.37 mg) of Pd(OAc)₂ at 60° C. The corresponding product 2a wasisolated by distillation in excellent yield and high enantioselectivity(Table 5, entry 1). Similarly, tetralone substrate 1b was subjected toenantioselective allylic alkylation conditions at 40° C. on a 20 mmolscale (4.89 g). The desired product 2b was purified by flashchromatography and isolated in 95% yield and 88% ee (Table 5, entry 2).

TABLE 5 Scale-up experiments.

Scale Pd Entry Substrate [mol] T [° C.] [mol %] Yield [%] ee [%] 1Cyclo- 0.01 60 0.150 95 ^(a)) 89 ^(c)) hexanone 1a 2 Tetralone 1b 0.0240 0.125 95 ^(b)) 88^(d)) ^(a)) Isolated yield, purification bydistillation. ^(b)) Isolated yield, purification by flashchromatography. ^(c)) Enantiomeric excess measured by chiral GC.^(d))Enantiomeric excess measured by chiral SFC.

Example 6. Ligand Loading and Reaction Concentration

Six experiments were conducted, employing different quantities ofligand, from 0.20 mol % to 1.0 mol %, in the presence of 0.10 mol %Pd(OAc)₂ (Table 6). A ligand loading of 0.40 mol %, which corresponds toa 4-fold excess of ligand with respect to palladium, was sufficient toprovide the desired product in quantitative yield and highenantioselectivity (Table 6, entry 4). Only at a loading of 0.20 mol %of ligand 3 a slight decrease in enantioselectivity was observed (Table6, entry 5).

TABLE 6 Assessment of the ligand loading for the decarboxylative allylicalkylation.

Entry Ligand 3 [mol %] Yield [%] ^(a)) ee [%] ^(b)) 1 1.00 99 88 2 0.8099 89 3 0.60 99 88 4 0.40 99 88 5 0.20 99 86 ^(a)) GC yield relative toan internal standard (tridecane). ^(b)) Enantiomeric excess measured bychiral GC.

Finally, we investigated the influence of concentration on reactivity. Abrief study across five different substrate concentrations was executed(Table 7).

TABLE 7 Assessment of the reaction concentration.

Entry concentration [M] Yield [%] ^(a)) ee [%] ^(b)) 1 0.40 99 88 2 0.2099 88 3 0.10 99 89 4 0.05 99 89 5 0.033 91 87 ^(a)) GC yield relative toan internal standard (tridecane). ^(b)) Enantiomeric excess measured bychiral GC.

We were pleased to find that the decarboxylative alkylation reactioncould be performed in high concentrations of up to 0.40 M without anynegative impact on yield or enantiomeric excess (Table 7, entry 1). Whenthe reaction was performed at higher dilution (0.033 M) a slightdecrease in yield and optical purity was observed (Table 7, entry 5).

Example 7. Lactams as Substrates

The decarboxylative allylic alkylation of lactams is particularly usefuland important, given the prevalence of quaternary N-heterocycles inbiologically active alkaloids and their potential importance inpharmaceutical agents.^([11]) Initial experiments suggested that higherpalladium loadings were required for the decarboxylative allylicalkylation of piperidinones. Consequently, a brief study was performedto determine the minimal palladium loading needed to efficientlycatalyze the reaction (Table 8). The electron-poor ligand(S)—(CF₃)₃-t-BuPHOX 4 was applied in the presence of varying amounts ofPd(OAc)₂ in TBME at 60° C.

TABLE 8 Assessment of the palladium loading for the decarboxylativeallylic alkylation of lactams.

Entry Pd [mol %] 4 [mol %] Yield [%] ^(a)) ee [%] ^(b)) 1 0.50 5.0 87 962 0.30 3.0 85 97 3 0.10 1.0 77 84 ^(a)) GC yield relative to an internalstandard (tridecane). ^(b)) Enantiomeric excess measured by HPLC.

At 0.10 mol % of Pd(OAc)₂ the desired product was obtained in only 77%yield and a reduced enantioselectivity of 84% ee. (Table 8, entry 3)Nevertheless, a catalyst concentration of only 0.30 mol % was sufficientto render the chiral lactam 6a in 85% yield and 97% ee (Table 8, entry2). Compared to the original report, in which 5.0 mol % of Pd₂(dba)₃were applied, this constitutes a more than thirtyfold decrease inpalladium loading.

Example & Additional Substrate Studies

To demonstrate the broad applicability of this novel protocol, a totaloften compounds were subjected to the improved reaction parameters(Table 9). Asymmetric allylic alkylation to generate products 2a, 2b and6a was discussed previously in detail (Table 9, entries 1-3).Allylmethylpiperidinone 6b and allylfluoropiperidinone 6d weresynthesized in a similar fashion. Yields of 81% and 80% respectively,and enantioselectivities of up to 99% could be obtained (Table 9, entry4 and 6). In the latter case, a catalyst loading as low as 0.125 mol %was sufficient to yield the product in near to perfectenantioselectivity. Despite the 80-fold reduction in palladium loadingcompared to the original procedure, no erosion of enantioselectivity wasobserved (Table 9, entry 6).

Gratifyingly, the novel allylic alkylation protocol could be applied toseven-membered rings as well; however, despite a near quantitative yieldonly reduced enantiomeric excess of 70% was observed for ketone 2c(Table 9, entry 7). Nevertheless, seven-membered caprolactam 6e wasisolated in 95% yield and high enantioselectivity (Table 9, entry 8).Notably, despite the dilution, cyclohexylketal 2d was generated in 79%yield and good enantioselectivity through intermolecular allylicalkylation of the corresponding silyl enol ether and allylmethanesulfonate (Table 9, entry 9).

Finally, cyclohexanedione 2e, which is a critical intermediate in thesynthesis of (−)-cyanthiwigin F,^([12]) could be accessed through doubleenantioselective allylic alkylation of the bis(□-ketoester) 1e inexcellent yield and near perfect enantioselectivity using only 0.25 mol% palladium. This corresponds to 5% of the palladium loading used in theoriginal protocol. Despite the considerable reduction in catalystconcentration the yield for this reaction was improved to 97% (Table 9,entry 10).

TABLE 9 Scope of the decarboxylative allylic alkylation.^(a)) EntryProduct Protocol Pd [mol %] Yield [%] ee [%] 1

old new  5.00  0.125 89 99 ^(b)) 88 89 2

old new  8.00  0.125 97 85 ^(b)) 92 89 3

old new 10.0  0.30 97 85 ^(f)) 99 97 4

old new 10.0  0.50 85 81 ^(f)) 99 95 5

old new 10.0  0.125 91 99 ^(f)) 94 88 6

old new 10.0  0.125 89 80 ^(f)) 99 99 7

old new  5.00  0.10 83 97 ^(e), f)) 87 70 8

old new  5.00  0.125 83 95 ^(f)) 93 90 9

old new —  0.10 — 79 ^(c), e), f)) — 90 10

old new  5.00  0.25 78 97 ^(d), e), f), h)) 99 99 ^(g)) ^(a))Conditions:Reactions were performed according to the “general procedure” in TBME at60° C. with a tenfold excess of ligand 3 with respect to Pd. b)Temperature: 40° C. c) Temperature: 32° C. d) Temperature: 27° C. e)Reaction performed in toluene. f) Ligand 4 was used. g) Diketone 2e wasobtained in 4.85:1.00 d.r. h) Isolated yield. GC yield relative to aninternal standard (tridecane). Enantiomeric excess measured by chiralGC, HPLC or SFC.

Example 9. Experimental Procedures Low Pd-Loading Allylic AlkylationReactions—General Method

In a nitrogen-filled glove box, Pd(OAc)₂ (1.1 mg, 4.9 μmol) was weighedinto a 20 mL scintillation vial and dissolved in TBME (20 mL). In aseparate 1-dram vial, (S)-t-BuPHOX (1.9 mg, 4.9 μmol) was dissolved inTBME (1 mL). To a 2-dram vial equipped with a magnetic stirbar, 1.02 mLof the Pd(OAc)₂ solution was added (56 μg, 0.25 μmol, 0.125 mol %)followed by 0.51 mL of the (S)-t-BuPHOX solution (0.97 mg, 2.5 μmol,1.25 mol %). This mixture was stirred at ambient temperature (28° C.) inthe glove box for 30-40 min. Substrate (0.20 mmol, 1.0 equiv) was takenup in TBME (0.5 mL) and added to the stirring catalyst solution. Forreactions analyzed by GC, tridecane (24 μL, 0.1 mmol, 0.5 equiv) wasadded. The reaction was sealed with a Teflon-lined cap, removed from theglove box and stirred at the indicated temperature for the indicatedperiod of time. At this point, the reaction was analyzed by GC, orpassed through a silica plug, concentrated in vacuo, and purified bycolumn chromatography.

(S)-2-allyl-2-methylcyclohexan-1-one (2a)

Synthesized according to the general method from cyclohexanone 1a. Thereaction was passed through a plug of SiO₂ and analyzed by GC (99%yield). The product could be isolated by column chromatography (SiO₂, 5%Et₂O in pentane) as a colorless oil and matched previously reportedcharacterization data.

(S)-2-allyl-2-methyl-3,4-dihydronaphthalen-1(2H)-one (2b)

Synthesized according to the general method from tetralone 1b. Productwas isolated by column chromatography (SiO₂, 5-10% Et₂O in hexanes) as apale yellow oil (85% yield) and matched previously reportedcharacterization data.

(S)-2-allyl-2-methylcycloheptan-1-one (2c)

Synthesized according to the general method from cycloheptanone 1c using1.0 mol % (S)-t-BuPHOX and 0.10 mol % Pd(OAc)₂ in toluene at 60° C. for10 h. Product was isolated by column chromatography (SiO₂, 3% Et₂O inpentane) as a colorless oil (97% yield) and matched previously reportedcharacterization data.

(2R,5R)-2,5-diallyl-2,5-dimethylcyclohexane-1,4-dione (2e)

Synthesized according to the general method from diketone 1e using 2.5mol % (S)—(CF₃)₃-t-BuPHOX and 0.25 mol % Pd(OAc)₂ in toluene at 25° C.for 19 h. Product was isolated by column chromatography (SiO₂, 3% EtOAcin hexanes) as a colorless oil (97% yield) and matched previouslyreported characterization data.

(S)-3-allyl-1-benzoyl-3-ethylpiperidin-2-one (6a)

Synthesized according to the general method from lactam 5a using 3.0 mol% (S)—(CF₃)₃-t-BuPHOX and 0.30 mol % Pd(OAc)₂. Product was isolated bycolumn chromatography (SiO₂, 15-20% Et₂O in hexanes) as a colorless oil(85% yield) and matched previously reported characterization data.

(S)-3-allyl-1-benzoyl-3-methylpiperidin-2-one (6b)

Synthesized according to the general method from lactam 5b using 5.0 mol% (S)—(CF₃)₃-t-BuPHOX and 0.50 mol % Pd(OAc)₂. Product was isolated bycolumn chromatography (SiO₂, 5-10% Et₂O in hexanes) as a colorless oil(81% yield) and matched previously reported characterization data.

(S)-3-allyl-1-benzoyl-3-methylpiperidine-2,6-dione (6c)

Synthesized according to the general method from imide 5c using 1.25 mol% (S)—(CF₃)₃-t-BuPHOX and 0.125 mol % Pd(OAc)₂. Product was isolated bycolumn chromatography (SiO₂, 10-20% EtOAc in hexanes) as a colorless oil(99% yield) and matched previously reported characterization data.

(R)-3-allyl-1-benzoyl-3-fluoropiperidin-2-one (6d)

Synthesized according to the general method from lactam 5d using 1.25mol % (S)—(CF₃)₃-t-BuPHOX and 0.125 mol % Pd(OAc)₂. Product was isolatedby column chromatography (SiO₂, 10-20% EtOAc in hexanes) as a colorlessoil (80% yield) and matched previously reported characterization data.

(S)-3-allyl-1-(4-methoxybenzoyl)-3-methylazepan-2-one (6e)

Synthesized according to the general method from lactam 5e using 1.25mol % (S)—(CF₃)₃-t-BuPHOX and 0.125 mol % Pd(OAc)₂. Product was isolatedby column chromatography (SiO₂, 10-20% EtOAc in hexanes) as a colorlessoil (95% yield) and matched previously reported characterization data.

(S)-2-allyl-2-methyl-1,5-dioxaspiro[5.5]undecan-3-one (2d)

A 20 mL vial was soaked in a 20:1 isopropanol:toluene bath saturatedwith potassium hydroxide for 12 h, rinsed with deionized water, acetone,and dried in a 120° C. oven overnight. The hot vial was the cycled intoa nitrogen-filled glovebox and allowed to cool to ambient temperature.The vial was then charged Bu₄NPh₃SiF₂ (TBAT, 184 mg, 0.34 mmol, 1.00equiv) and toluene (12.0 mL, 0.033 M) with stirring, followed byPd(OAc)₂ (0.10 mg, 0.0004 mmol, 1.0 mg/mL in toluene, 0.00125 equiv) and(S)—(CF₃)₃-t-BuPHOX (2.37 mg, 0.004 mmol, 10 mg/mL in toluene, 0.0125equiv). The reaction vessel was immediately introduced to a heat blockat 32° C. and allowed to stir for 20 minutes. To the resulting tansolution was added allylmesylate (57 mg, 0.42 mmol, 1.20 equiv) quicklydropwise. After 3 minutes, silyl enol ether 1d (100 mg, 0.34 mmol, 1.00equiv) was added quickly dropwise. Upon complete consumption of the enolether (as determined by TLC analysis, 24 h), the resultant tan solutionwas removed from the heat block, allowed to cool to ambient temperature,and removed from the glove box. The reaction mixture was filteredthrough a pad of SiO₂ using hexanes eluent to remove toluene, followedby Et₂O eluent to isolate the volatile reaction products. The filtratewas concentrated in vacuo to a brown oil which was subsequently purifiedby flash chromatography (SiO₂, 4% Et₂O in hexanes) to afford volatileallyl ketal 2d (60 mg, 79% yield) as a clear, colorless oil: R_(f)=0.35(19:1 hexanes:Et₂O); ¹H NMR (400 MHz, CDCl₃), 5.85 (ddt, J=17.4, 10.3,7.2 Hz, 1H), 5.14-5.03 (m, 2H), 4.20 (d, J=1.0 Hz, 2H), 2.51 (ddt,J=14.0, 7.2, 1.2 Hz, 1H), 2.41 (ddt, J=14.0, 7.2, 1.2 Hz, 1H), 1.87-1.42(m, 10H), 1.38 (s, 3H); ¹³C NMR (101 MHz, CDCl₃), 211.4, 132.7, 118.8,100.0, 82.0, 66.6, 44.0, 35.8, 35.5, 25.4, 24.7, 23.1, 23.1; IR (NeatFilm, NaCl) 2938, 2860, 1742, 1446, 1365, 1259, 1159, 1112, 1056, 1000,943, 916, 826 cm⁻¹; HRMS (EI+) m/z calc'd for C₁₃H₂₀O₃ [M•]⁺: 224.1412,found 224.1409; [α]_(D) ^(25.0)−45.9° (c 1.10, CHCl₃, 90% ee).

Scale Up Procedures

(s)-2-allyl-2-methyl-cyclohexanone (2a)

An oven-dried 250 mL round-bottom flask equipped with a magnetic stirbar was fitted with a rubber septum and cooled to room temperature underan atmosphere of argon. To the flask were added Pd(OAc)₂ (3.37 mg, 15μmol, 0.150 mol %) and (S)-t-BuPHOX (58 mg, 150 μmol, 1.50 mol %). Theflask was evacuated and backfilled with argon three times. TBME (90 mL)was added to the flask and the mixture was stirred for 30 min in a 40°C. oil bath. Substrate 1a (1.96 g, 10.0 mmol, 1.0 equiv) was taken up inTBME (10 mL) and added to the stirring catalyst solution. The reactionwas stirred for 16 h at 60° C., the reaction mixture was passed througha pad of silica gel (2 cm diameter×3 cm height) and rinsed with diethylether (50 mL). The filtrate was concentrated in vacuo and the remainingoil was distilled through a short path apparatus (bp. 91-93° C./16 mmHg)into a receiving flask immersed in an ice water bath to yield product 2aas a pale yellow oil (1.45 g, 9.50 mmol, 95% yield). The product wasdetermined to be in 89% ee by chiral GC and matched previously reportedcharacterization data.

(S)-2-allyl-2-methyl-3,4-dihydronaphthalen-1(2H)-one (2b)

An oven-dried 500 mL round-bottom flask equipped with a magnetic stirbar was fitted with a rubber septum and cooled to room temperature underan atmosphere of argon. To the flask were added Pd(OAc)₂ (5.6 mg, 25μmol, 0.125 mol %) and (S)-t-BuPHOX (97 mg, 250 μmol, 1.25 mol %). Theflask was evacuated and backfilled with argon three times. TBME (190 mL)was added to the flask and the mixture was stirred for 30 min in a 40°C. oil bath. Substrate 1b (4.89 g, 20.0 mmol, 1.0 equiv) was taken up inTBME (10 mL) and added to the stirring catalyst solution. The reactionwas stirred for 16 h, concentrated in vacuo and purified by columnchromatography (SiO₂, 5-10-20% Et₂O/hexanes) to yield product 2b as apale yellow oil (3.81 g, 19.0 mmol, 95% yield). The product wasdetermined to be in 88% ee by chiral SFC and matched previously reportedcharacterization data.

REFERENCES

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INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference. In case of conflict, the present application, including anydefinitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1-40. (canceled)
 41. A method for the preparation of a compound offormula (I):

the preparing comprising treating, with a Pd(II) catalyst in an organicsolvent, (i) a compound of formula (II) or (III) or a salt thereof:

or (ii) a compound of formula (IV) or (V) or a salt thereof:

and a compound of formula (X):

wherein the Pd(II) catalyst is used in an amount from about 0.01 mol %to about 3 mol % relative to the compound of formula (II), (III), (IV),or (V), wherein, as valence and stability permit, R¹ represents hydrogenor substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl,(5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3-to 10-membered heterocyclyl, alkoxy, amino, or halo; R², R³, R⁴, R⁵,R¹², R¹³, R¹⁴, and R¹⁵ are independently selected for each occurrencefrom hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group,thioether group, ester group, amide, thioester group, carbonate group,carbamate group, urea group, sulfonate group, sulfone group, sulfoxidegroup, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-memberedheterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl,(cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl; Wrepresents, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—, —C(O)—, —CR⁷═,or —N═; R⁶ represents hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-memberedheteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl,—C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-memberedheteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl),—C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or —NR¹⁰R¹¹; R⁷ and R⁸ eachindependently represent hydrogen, hydroxyl, halo, nitro, alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-memberedheteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-memberedheterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl,cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy,alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,mercaptoalkyl, haloalkyl, ether group, thioether group, ester group,amido, thioester group, carbonate group, carbamate group, urea group,sulfonate group, sulfone group, sulfoxide group, sulfonamide group,acyl, acyloxy, or acylamino; or R⁶, R⁷, and R⁸ taken together with asubstituent on ring A and the intervening atoms, form an optionallysubstituted aryl, 5- to 10-membered heteroaryl, cycloalkyl,cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-memberedheterocyclyl)alkenyl; R¹⁰ and R¹¹ are independently selected for eachoccurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl,aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5-to 10-membered heterocyclyl, alkenyl, and alkynyl; and ring A representsan optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl,cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, wherein eachheteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N,O, and S; and wherein substituents on the alkyl, haloalkyl, alkenyl,alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5-to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,alkoxy, or amino are selected from halo, hydroxyl, carboxyl,alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,thioformate group, alkoxy, phosphate group, phosphonate group,phosphinate, amino, amido, amidine group, imine group, cyano, nitro,azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group,sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl,aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 42.A method of preparing a pharmaceutical agent, comprising preparing acompound of formula (I):

the preparing comprising treating, with a Pd(II) catalyst in an organicsolvent, (i) a compound of formula (II) or (III) or a salt thereof:

or (ii) a compound of formula (IV) or (V) or a salt thereof:

and a compound of formula (X):

wherein the Pd(II) catalyst is used in an amount from about 0.01 mol %to about 3 mol % relative to the compound of formula (II), (III), (IV),or (V), wherein, as valence and stability permit, R¹ represents hydrogenor substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl,(5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3-to 10-membered heterocyclyl, alkoxy, amino, or halo; R², R³, R⁴, R⁵,R¹², R¹³, R¹⁴, and R¹⁵ are independently selected for each occurrencefrom hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano,carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio,hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group,thioether group, ester group, amide, thioester group, carbonate group,carbamate group, urea group, sulfonate group, sulfone group, sulfoxidegroup, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-memberedheterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl,(cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl; Wrepresents, as valence permits, —O—, —S—, —NR⁶—, —CR⁷R⁸—, —C(O)—, —CR⁷═,or —N═; R⁶ represents hydrogen or optionally substituted alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-memberedheteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl,—C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-memberedheteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl),—C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or —NR¹⁰R¹¹; R⁷ and R⁸ eachindependently represent hydrogen, hydroxyl, halo, nitro, alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-memberedheteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-memberedheterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl,cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy,alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,mercaptoalkyl, haloalkyl, ether group, thioether group, ester group,amido, thioester group, carbonate group, carbamate group, urea group,sulfonate group, sulfone group, sulfoxide group, sulfonamide group,acyl, acyloxy, or acylamino; or R⁶, R⁷, and R⁸ taken together with asubstituent on ring A and the intervening atoms, form an optionallysubstituted aryl, 5- to 10-membered heteroaryl, cycloalkyl,cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-memberedheterocyclyl)alkenyl; R¹⁰ and R¹¹ are independently selected for eachoccurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl,aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5-to 10-membered heterocyclyl, alkenyl, and alkynyl; and ring A representsan optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl,cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, wherein eachheteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N,O, and S; and wherein substituents on the alkyl, haloalkyl, alkenyl,alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5-to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,alkoxy, or amino are selected from halo, hydroxyl, carboxyl,alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,thioformate group, alkoxy, phosphate group, phosphonate group,phosphinate, amino, amido, amidine group, imine group, cyano, nitro,azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group,sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl,aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 43.A method comprising (a) preparing a compound of formula (I):

the preparing comprising treating with a Pd(II) catalyst in an organicsolvent, (i) a compound of formula (II) or (III) or a salt thereof:

or (ii) a compound of formula (IV) or (V) or a salt thereof:

and a compound of formula (X):

wherein the Pd(II) catalyst is used in an amount from about 0.01 mol %to about 3 mol % relative to the compound of formula (II), (III), (IV),or (V); and (b) synthesizing a pharmaceutical agent from the compound offormula (I), wherein, as valence and stability permit, R¹ representshydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl,aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-memberedheteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-memberedheterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, orhalo; R², R³, R⁴, R⁵, R¹², R¹³, R¹⁴, and R¹⁵ are independently selectedfor each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl,alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy,alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,mercaptoalkyl, ether group, thioether group, ester group, amide,thioester group, carbonate group, carbamate group, urea group, sulfonategroup, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy,acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-memberedheteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-memberedheterocyclyl)alkyl; W represents, as valence permits, —O—, —S—, —NR⁶—,—CR⁷R⁸—, —C(O)—, —CR⁷═, or —N═; R⁶ represents hydrogen or optionallysubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl,alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-memberedheteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl),—C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl),—C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)₂(aryl), —S(O)₂(alkyl),—S(O)₂(haloalkyl), —OR¹⁰, —SR¹⁰, or —NR¹⁰R¹¹; R⁷ and R⁸ eachindependently represent hydrogen, hydroxyl, halo, nitro, alkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-memberedheteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-memberedheterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl,cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy,alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl,mercaptoalkyl, haloalkyl, ether group, thioether group, ester group,amido, thioester group, carbonate group, carbamate group, urea group,sulfonate group, sulfone group, sulfoxide group, sulfonamide group,acyl, acyloxy, or acylamino; or R⁶, R⁷, and R⁸ taken together with asubstituent on ring A and the intervening atoms, form an optionallysubstituted aryl, 5- to 10-membered heteroaryl, cycloalkyl,cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-memberedheterocyclyl)alkenyl; R¹⁰ and R¹¹ are independently selected for eachoccurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl,aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl,(cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5-to 10-membered heterocyclyl, alkenyl, and alkynyl; and ring A representsan optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl,cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl, wherein eachheteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N,O, and S; and wherein substituents on the alkyl, haloalkyl, alkenyl,alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5-to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl,alkoxy, or amino are selected from halo, hydroxyl, carboxyl,alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group,thioformate group, alkoxy, phosphate group, phosphonate group,phosphinate, amino, amido, amidine group, imine group, cyano, nitro,azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group,sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl,aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group. 44.The method of claim 43, wherein the compound of formula (I) isrepresented by formula (Ia):

and the compound of formula (II) is represented by formula (IIa):

and the compound of formula (III) is represented by formula (IIIa):

wherein: B, D, and E independently for each occurrence represent, asvalence permits, O, S, NR⁶, CR⁷R⁸, C(O), CR⁷, or N; provided that no twoadjacent occurrences of W, B, D, and E are NR⁶, O, S, or N; or any twooccurrences of R⁶, R⁷, and R⁸ on adjacent W, B, D, or E groups, takentogether with the intervening atoms, form an optionally substitutedaryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;each occurrence of

independently represents a double bond or a single bond as permitted byvalence; and m and n are integers each independently selected from 0, 1,and
 2. 45. The method of claim 44, wherein the sum of m and n is 0, 1,2, or
 3. 46. The method of claim 44, wherein each occurrence of W, B, D,and E is each independently —CR⁷R⁸—, or —CR⁷—, or —C(O)—.
 47. The methodof claim 46, wherein one occurrence of W, B, D, and E is —CR⁷R⁸— or—C(O)—, and the remaining three are —CR⁷R⁸—; optionally wherein R⁷ andR⁸, independently for each occurrence, are selected from hydrogen,hydroxyl, halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5-to 10-membered heteroaryl, 5- to 10-membered heteroaryl)alkyl, (5- to10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl,alkynyl, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, and amido. 48.The method of claim 44, wherein at least two adjacent occurrences of W,B, D, and E are —CR⁷—.
 49. The method of claim 48, wherein W and B areeach —CR⁷— and m is 1; optionally wherein R⁷ is independently selectedfor each occurrence from hydrogen, hydroxyl, halo, alkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroarylheteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-memberedheterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl,amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or theoccurrence of R⁷ on W and the occurrence of R⁷ on B are taken togetherto form an optionally substituted aryl, 5- to 10-membered heteroaryl,cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl.
 50. The methodof claim 44, wherein at least one occurrence of W, B, D, and E is —NR⁶—.51. The method of claim 50, wherein W is —NR⁶—; optionally wherein atleast one occurrence of the remaining B, D, and E is —NR⁶— or O.
 52. Themethod of claim 50, wherein R⁶ represents, independently for eachoccurrence, hydrogen or optionally substituted alkyl, aralkyl, (5- to10-membered heteroaryl)alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl,—C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), or —S(O)₂(aryl).
 53. Themethod of claim 44, wherein at least one occurrence of W, B, D, and E is—O—.
 54. The method of claim 43, wherein W represents —O—, —S—, —NR⁶—,—CR⁷R⁸—, or —CR⁷═.
 55. The method of claim 43, wherein R², R³, R⁴, R⁵,R¹², R¹³, R¹⁴, and R¹⁵ are each hydrogen.
 56. The method of claim 43,wherein R¹ represents substituted or unsubstituted alkyl, alkenyl,alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, or halo.57. The method of claim 43, wherein the Pd(II) catalyst is selected fromPd(OC(O)R)₂, Pd(OAc)₂, PdCl₂, Pd(PhCN)₂Cl₂, Pd(CH₃CN)₂Cl₂, PdBr₂,Pd(acac)₂, [Pd(allyl)Cl]₂, Pd(TFA)₂, and pre-formed Pd(II)-ligandcomplex; wherein R^(c) is optionally substituted alkyl, alkenyl,alkynyl, aryl, 5- to 10-membered heteroaryl, aralkyl, (5- to 10-memberedheteroaryl)alkyl, cycloalkyl, 5- to 10-membered heterocyclyl,(cycloalkyl)alkyl, or (5- to 10-membered heterocyclyl)alkyl.
 58. Themethod of claim 43, wherein the Pd(II) catalyst is Pd(OAc)₂.
 59. Themethod of claim 43, wherein the Pd(II) catalyst is used in an amountfrom about 0.02 mol % to about 2.5 mol % relative to the compound offormula (II), (III), (IV), or (V).
 60. The method of claim 43, whereinthe Pd(II) catalyst further comprises a chiral ligand.
 61. The method ofclaim 60, wherein the chiral ligand is used in an amount from about 0.1mol % to about 100 mol % relative to the compound of formula (II),(III), (IV), or (V).
 62. The method of claim 43, wherein the organicsolvent is selected from methyl tert-butyl ether, toluene, and2-methyltetrahydrofuran.
 63. The method of claim 43, whereby thecompound of formula (I) is enantioenriched.